Medicinal chemists are constantly seeking and developing synthetic procedures for the introduction of functional groups into compounds showing potential biological activity in order to fine-tune the properties of said compounds. For instance, it has been shown that the introduction of a trifluoromethyl group into the scaffold of a biologically active compound tends to enhance the biological activity of the same, which in turn, leads to the development of several synthetic methodologies and reagents for the introduction of the trifluoromethyl group in the last synthetic step. In the same manner, the introduction of labelled atoms into existing compounds, such as 11C or 18F, allows preparing radiotracers for applications in medical imaging (Positron Emission Tomography). In both cases, suitable synthetic methods and reagents are required for the introduction of functional groups of interest into a molecular scaffold. Currently, late-stage functionalization approaches, as those reviewed by Cernak and co-workers have been developed for the introduction of various functional groups, for example into aromatic C—H bonds.
On the other hand, the radicals derived from the diazomethyl group, such as 1-diazo-2-alkyloxy-2-oxoethyl or 1-diazo-2,2,2-trifluoroethyl, represent a highly versatile functional group, since the diazo functionality represents a carbene precursor. Such functional groups are commonly found in starting materials for a broad number of chemical reactions such as cyclopropanation, cycloaddition, oxidation, amination, halogenation, arylation and epoxidation among others, as described for instance in Ford et al. The diazomethyl functional group therefore represents a good starting point in the preparation of compounds with high molecular diversity from one sole starting material, making it suitable for applications in the discovery and development of biologically active molecules, such as agrochemicals and drugs.
However, the introduction of a diazomethyl group into an aromatic C—H bond in one sole synthetic step has not yet been reported. Several methods have been reported in the state of the art for the introduction of a diazomethyl group into an aromatic C—H bond. Such methods are multi-step sequences, and usually involve a Friedel-Crafts acylation reaction (preparation of aryl ketones from aromatic substrates and acid chlorides), followed by a treatment with hydrazine and subsequent transformation of the resulting hydrazone compound to the desired diazomethyl derivative. This multi-step synthetic sequence typically requires using harsh conditions of reaction and unstable or sensitive reagents (such as hydrazine, Lewis acids or hydrazone oxidizing agent), making it unsuitable for highly functionalized starting materials and late-stage functionalization approach.
Furthermore, several hypervalent diazomethyliodine compounds have been reported in the literature. Schnaars et al. reported a series of alpha-aryl iodonio diazo derivatives and their use as sources of diazomethyl groups in nucleophilic substitution reactions, in particular in the preparation of halogenated diazomethyl derivatives. Furthermore, Weiss et al. described similar reagents for use as electrophiles in nucleophilic substitution reactions. The use of these compounds in reactions of functionalization of aromatic C—H bonds comprised in a reaction substrate has however not been reported. The reported alpha-aryl iodonio diazo derivatives have the following formulae:

where R′ is ethyl or tert-butyl. In both cases, these compounds are used in reaction with substrates comprising a nucleophilic heteroatom which attacks the carbon atom of the diazomethyl iodine derivative to form a product wherein the diazomethyl radical is linked to the aforementioned heteroatom.
Furthermore, Li et al. also review the use of benzoiodoxolone reagents in the formation of C—C bond. The authors are silent about the use of these compounds in the diazomethylation of aromatic C—H bonds.
Thus, even though several synthetic tools have been reported for late-stage functionalization of organic compounds and for the insertion of diazomethyl radicals into aromatic C—H bonds, there is still the need for methods and reagents for the insertion of diazomethyl groups into aromatic C—H bonds that is carried out in one synthetic step and in mild conditions, and that exhibits high functional group tolerance.